1. Field of the Invention
The present invention relates to optically active trans-2-aryl-1-cyclohexanol derivatives and a process for production thereof.
2. Description of the Prior Art
Racemic trans-2-aryl 1-cyclohexanol derivatives such as trans-2- (2-benzyloxyphenyl) -1 -cyclohexanol are known as synthetic materials for several types of aminopropanol. However, the optically active compounds are not yet known (DE3427241), and these compounds are new compounds which are synthesized for the first time by the inventors of the present invention.
It is known that conventionally known optically active trans-2-phenyl-1-cyclohexanol, which is a similar compound for the compounds of the present invention, is useful as an asymmetric source of asymmetric Diels-Alder reaction. For example, Green et al. synthesized (-)-.alpha.-and (+)-.beta.-Cuperenone (J. Am. Chem, Soc., 109, 4752(1987)).
The compounds of the present invention are naturally useful as the asymmetric source of asymmetric Diels-Alder reaction, considering the steric configuration, higher asymmetric yield will be expected than that of optically active trans-2-phenyl-1-cyclohexanol. Moreover, the compounds of the present invention will be expected not only to be useful asymmetric sources but also as useful starting materials for synthesizing physiological active materials by using the skeleton.
Namely, the skeleton represented by R.sup.1 in the general formula (I) of the compounds of the present invention acts as a protective group for a phenolic hydroxyl group and has wide selectivity of functional groups. The hydroxyl group on the cyclohexane ring also has the same characteristics. The compounds have two hydroxyl groups in a molecule, so that it will be expected to use them widely in comparison with known optically active trans-2-phenyl-1-cyclohexanol.
As an example of the compounds of the present invention, 2- (2-benzyloxyphenyl)-1-cyclohexanol (a compound described in Example 2) is useful as a starting material of RG-1 2915 which is a pharmaceutical as shown in the following flow chart (U.S. Pat. No. 5,086,179).
Namely, after a hydroxy group is introduced into a deprotected group (for example, a mesyloxy group), a benzyl group is deprotected by catalytic reduction, and intramolecular cyclization can be conducted by nucleophilic reaction. Then, the resulting compound is treated by chlorination, acylation and haloform reaction to introduce a carboxy group into the benzene skeleton, and a principle skeleton can be obtained. Finally, 3-aminoquinuclidine is reacted with the obtained compound to form an acid-amide bond, and RG-1291 5 can be obtained.
RG-1 2915 exhibits 5HT3-antagonist properties including unique CNS (center nervous system), anti-emeric and gastric prokinetic activity, and is void of any significant D.sub.2 receptor binding affinity.
Further, it is known that only one of the optical isomers of the compounds has good activity. Accordingly, the steric configuration of the starting materials is very important. ##STR3##
For synthesizing optically active trans-2-phenyl-1cyclohexanol which is similar to the compounds of the present invention, an optical resolution method using transesterification of enzymes disclosed by Yoshida et al., Japanese Patent Application No. 1-209958(1989), an asymmetric hydroboration method reported by Brown et al., J. Org. Chem., 47, 5074(1982) etc., an optical resolution method using hydrobytic action of an enzyme described by Robert et al., Chimia, 40, 318(1986) and the like are known. These methods can be conceived by a person having ordinary skill in the art to which said subject matter pertains to synthesize the compounds of the present invention.
The process of the present invention looks like the application of the method disclosed by Yoshida et al. at first glance. However, a distinction should be drawn between the process of the present invention and the method of Yoshida et al., because different substrates are used, although a similar technique using enzymes is adopted.
The reason is as follows. For example, asymmetric reduction of .beta.-ketoesters by using baker's yeast is well-known. In the reduction of ethyl acetoacetate, the optical yield is 90% ee (Zeebach et al., Helv. Chim. Acta, 60, 1175(1 977)), while in the case of ethyl propionylacetate, the optical yield is only 40% ee (Fleiter et al., Helv. Chim. Acta, 62, 2829(1 979)). Further, in the case of .gamma.-chloroeacetoacetic acid ester wherein an alkyl group of the ester is pentyl, the optical yield is about 0% ee, while the optical yield is more than 95% ee in a hexyl group and alkyl groups having more than 7 carbon atoms (Seen et al., J. Am. Chem. Soc., 105, 5925(1983)). Accordingly, the yield is remarkably changed according to substrates.
Similarly, in the method of asymmetric synthesis, it is very difficult to anticipate change of the yield according to substrates, so that the possibility of the application to the compounds of the present invention is found for the first time by trial and error.
As described above, it is desired to develop a method for efficiently obtaining in large quantities optically active trans-2-aryl-1-cyclohexanol derivatives useful as starting materials for physiologically active materials and having wide application to the asymmetric synthesis.
The inventors of the present invention conducted research for resolving the above problems and then successfully obtained optically active trans-2-aryl-1-cyclohexanol derivatives.